The Long Life Family Study (LLFS) has enrolled 4,953 participants in 539 pedigrees in the USA and Denmark that are enriched for exceptional longevity, and has measured them longitudinally in two extensive in-home visits measuring key healthy aging phenotypes in all of the major domains of the aging process. We have demonstrated through many publications that selecting on longevity in the first (proband) generation, results in the second (offspring) generation being much healthier than average in many key phenotypes. However, the pedigrees are heterogeneous by phenotype, with different families showing familial clustering of protection in cognition, grip strength, pulmonary function, blood pressure, etc. Further, comprehensive linkage analysis of the LLFS sample identifies extremely strong genetic linkage peaks for cross-sectional as well as longitudinal trajectory rates of change phenotypes for a wide variety of healthy aging domains such as exceptional cognitive performance and lack of Alzheimer?s disease. These peaks are NOT explained by GWAS SNPs (or those that can be imputed by GWAS). Pedigree specific LODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. We propose to do Whole Genome Sequencing on this unique cohort, to identify the rare protective variants driving these strong linkage peaks. We propose to continue longitudinal assessment of the cohort with a third in-person visit, which will allow us to assess potential non-linear patterns of aging, and adding formal assessment of dementia diagnosis for Alzheimer?s Disease and other dementia types, which will increase specificity and power to discover and follow- up on protective variants against Alzheimer?s Disease and other dementia diagnoses. For pedigrees driving multiple strong linkage peaks, we also propose to phenotypically measure the third generation (grandchildren), as these are likely to carry more copies of the rare protective alleles running in these families, which will exponentially increase our power to resolve them. Preliminary evidence from the Danish Medical Registry suggests that, at least in Denmark, the protection persists into this third generation, with significantly lower rates of medical conditions across the disease spectrum. We also propose to do extensive transcriptomics, methylomics, and proteomics on these selected high linkage pedigrees, to begin to move from ?statistically associated variants/loci? to the biological genes of action, since we expect most of the driving variants will be regulatory and non-coding. It is critical to find the modes of action of these rare protective variants. We also propose to do metabolomics on the entire LLFS cohort, longitudinally, with the goal of identifying novel biomarkers of healthy aging and resistance to diseases such as Alzheimer?s in this unusually heathy cohort. Combined with a systems biology/network approach to data integration of the proposed ?Big Data?, such biomarkers would improve our power to detect even more novel protective genetic variants and identify the genetic signatures and pathways of genes conferring protection in this unique cohort to prevent onset of major diseases such as diabetes, cardiovascular disease, cancer and Alzheimer?s Disease and other dementia types.